Mutations in BRCA genes are associated with 5% of all breast cancer (BC), and a larger proportion of young women with BC. Large rearrangements, not detectable by standard sequencing, account for up to 15% of deleterious BRCA mutations. The lifetime risk of developing BC associated with a BRCA mutation may be as high as 85%. We previously reported on the prevalence of deleterious BRCA mutations (31% of 110 families) in a Hispanic high-risk clinic in Los Angeles, and also identified a unique recurrent large BRCA1 rearrangement (deletion of BRCA1 exons 9-12). BRCA1 185delAG was detected in independent Hispanic families, and through haplotyping we established that they shared a common ancestral origin with Jewish carrier families. Using a new high-throughput Sequenom(R) platform, we developed a prototype multiplex panel to test for recurrent BRCA mutations, including 185delAG, and a 3-primer assay to test for the BRCA1 rearrangement mutation. We developed and piloted this 18 mutation panel in the clinical genetic cancer risk assessment setting;the panel detected 57% of deleterious mutations. Commercial confirmation of a known mutation is relatively cost-efficient. Hypotheses: 1) Using a panel of recurrent BRCA mutations found in women of Hispanic ancestry to pre-screen samples will demonstrate clinical utility and reduce genotyping cost;2) Studying BRCA mutations from high-risk clinics serving Hispanic populations, from published literature and public databases, and from additional population-based cohorts will enable comprehensive characterization of BRCA mutations in Hispanics;3) The characterization of the ancestral background of recurrent BRCA mutations will enhance the value of our Hispanic mutation panel. Methods: An expended panel will be created to account for up to 90% of BRCA mutations among Hispanic populations. Blood/DNA samples and clinical data from Hispanic patients will be collected from a new consortium of high-risk clinics and population-based cohorts. 628 samples from high-risk clinics will be prospectively analyzed for BRCA mutations using our revised Hispanic Mutation Panel prior to BRCA full sequencing. 909 samples from 2 high-risk clinics and 2 population-based cohorts will be analyzed for the BRCA1 large rearrangement del (ex9-12). We will use ancestral informative markers to characterize the admixture of carriers of recurrent BRCA mutations and the ancestral origin of the mutations. Haplotyping will be used to estimate the age of the del (ex 9-12) mutation. Summary: BC is the most common cancer and the leading cause of cancer death in Hispanic women. The unique BRCA panel will reduce testing cost for high-risk Hispanics, and enable more women to benefit from limited resources. Knowledge of the ancestry of recurrent mutations may make the panel more effective. Understanding the genetic etiology of BC in Hispanics will enable screening and cancer prevention. PUBLIC HEALTH RELEVANCE: Breast Cancer is the most common cancer and the leading cause of cancer death in Hispanic women. A unique Hispanic BRCA mutation test will reduce the BRCA testing cost for high-risk Hispanics, and enable more women to benefit from limited resources. This study may lead to more efficient breast cancer risk assessment for Hispanic women, which will allow them to make informed decisions to reduce the risk of advanced breast cancers.